Isosexual precocious puberty is an uncommonly seen phenomenon, and this can occur due to various causes – central type due to stimulation of the hypothalamo-pitutary-gonadal axis or peripheral type due to sex hormone secretion independent of hypothalamic stimulation. Tumors are rare causes of sexual precocity, and initial presentation of mediastinal germ cell tumors (GCT) as precocious puberty is very uncommon.

Case 1: 10-year-old boy was referred to us with history of change in voice noted by parents one year back, followed sometime later by appearance of pubic hair and sudden increase in stature. He had been evaluated with multiple investigations including CT scan abdomen, bone scan and MRI of head, which were normal. Meanwhile, patient developed cough and breathlessness, and chest X-ray revealed mediastinal mass, from which trucut biopsy was done. On examination, the boy was pale and tachypneic, had decreased breath sounds over right axillary and mammary areas, and firm hepatomegaly. His phenotype was normal, and he had enlarged gonads, thick pubic hair and deep voice. Complete blood counts and liver and renal function tests were normal. CT scan showed large soft tissue opacity occupying the anterior and middle mediastinum, opacification of right upper lobe of lung and rounded well-defined soft tissue masses in both lung fields suggestive of metastases. Ultrasound scan of abdomen showed hypoechoic area in right lobe of liver suggestive of metastases and right sided pleural effusion. Thyroid function tests, FSH, estradiol and testosterone were normal. Serum tumour markers revealed β-HCG of more than 50,000 mIU/mL and AFP of 269 ng/mL. The biopsy slide review was suggestive of germ cell tumour.

Patient was treated with chemotherapy using ifosfamide, etoposide and carboplatin, with good clinical response, as assessed with decreasing tumour marker levels, reduction in symptoms, decrease in mass size and disappearance of liver lesion. After 6 courses of chemotherapy, patient underwent resection of residual mediastinal mass. Follow-up CT scan of chest after 3 months showed no tumor or lung metastases, and tumor markers were normal. Patient is on regular follow-up for past 7 years, and is doing well.

Patient received chemotherapy with cisplatin, bleomycin and etoposide every 3 weeks. After 4 cycles of chemotherapy, his tumor markers were normal (AFP 4.6 ng/mL, β-HCG 7.5 mIU/mL) and chest scan still showed residual tumour with calcification and multiple lung metastases. He received two more courses of cisplatin and etoposide, and then underwent excision of residual mediastinal mass. Post-op scans showed multiple mediastinal nodes and pulmonary metastases, which disappeared on follow-up scans 6 months later. 3.5 years post treatment, he is free of disease.

Cause of precocious puberty may range from variant of normal to pathological causes with significant risk of morbidity and mortality like malignant germ cell tumors [1]. These tumors are infrequent in children, occurring at a rate of 2.4 cases per million children, representing approximately 1% of cancers diagnosed in persons younger than 15 years. [2] Only 1-2% of all GCTs in children occur in the mediastinum [3].

Mediastinal GCT patients may present with chest pain, dyspnea, superior vena cava syndrome, cough, weight loss, fever, night sweats, dysphagia, shoulder or arm pain and hoarseness, or can be an incidental finding of routine chest X-ray [3]. Nonseminomatous mediastinal GCTs may produce bioactive substances like alpha-fetoprotein and/or β-HCG, which may cause gynecomastia and precocious puberty due to elevated testosterone levels, secondary to stimulation of the testes by  β-HCG [4,5].

About 40 cases of mediastinal GCTs presenting as isosexual precocious puberty in patients with Klinefelter syndrome are reported [7]. However, it is rarely reported in boys with normal phenotype. Both our patients did not have Klinefelter syndrome.

Nonseminomatous mediastinal GCTs are faster growing and metastasize earlier than mediastinal seminomas [3]. Both our patients had advanced stage of disease at presentation. Histopathologically, HCG- secreting thoracic tumours reported are teratomas, choriocarcinomas, polyembryomas and teratocarcinomas [4,6,7]. In both our patients, histopathology after surgical resection was teratoma with nonviable elements and treatment changes.

Intensive cisplatin-based chemotherapy followed by resection of residual tumor was shown to yield survival rates of 48-73% in nonseminomatous MGCTs [3]. Surgical resection should include all gross disease with en bloc resection of all involved structures that can be sacrificed [10]. Though GCTs in general have a good outcome with treatment, prognosis of mediastinal GCT is not that satisfactory, especially with advanced stages. [10] This is because MGCTs are not as sensitive as other GCT to chemotherapy and bulky disease increases risk of poor outcome in the short term owing to respiratory failure [3].

There is a significant interaction between age and primary site in GCT, suggesting that patients older than 12 years of age with thoracic tumors are a biologically distinct group, at higher risk of mortality from tumour progression [8]. An intergroup POG/CCSG randomized trial found that these tumours often have incomplete regression with chemotherapy alone. Aggressive attempt at complete tumor resection should be offered to all patients even if bulky tumor persists after induction chemotherapy, with expectation of a significant salvage rate [9]. Both our patients were treated aggressively, and are free of disease three years post treatment.

Contributors: All authors contributed to literature search, patient care and drafting the manuscript.

Funding: Nil; Competing interests: None stated.

1. Cesario SK,　Hughes LA. Precocious puberty: a comprehensive review of literature. J Obstet Gynecol Neonatal Nurs.　2007;36:263-74.

2. Young Jr. JL, Ries LG,　Silverberg E, Horm JW,　Miller RW. Cancer incidence, survival, and mortality for children younger than age 15 years. Cancer. 1986;58:598-602.

3. Lack EE, Weinstein HJ, Welch KJ. Mediastinal germ cell tumours in childhood: A clinical and pathological study of 21 cases. J Thoracic Cardiovasc Surg. 1985; 89:826.

4. Bebb GG, Grannis FW Jr, Paz IB, Slovak ML, Chilcote R. Mediastinal germ cell tumor in a child with precocious puberty and Klinefelter syndrome. Ann Thorac Surg. 1998;66:547-8.

5. de Monleon JV, Simonin G, Pincemaille O. Precocious puberty secondary to an intramedullary germinoma. Arch Pediatr. 1999;6:46-9.

6. Konig R, Schonberger W, Grimm W. Mediastinal teratocarcinoma and hypophyseal stalk germinoma in a patient with Klinefelter syndrome. Klin Padiatr. 1990;202:53-6.

7. Hasle H, Jacobsen BB, Asschenfeldt P, Andersen K. Mediastinal germ cell tumour associated with Klinefelter syndrome. A report of case and review of literature. Eur J Pediatr. 1992;151:735-9.

8. Marina N,　London WB,　Frazier AL,　Lauer S,　Rescorla F,　Cushing B,　 et al. Prognostic factors in children with extragonadal malignant germ cell tumors: a pediatric intergroup study. J Clin Oncol.　2006;24:2544-8.

9. Billmire D,　Vinocur C,　Rescorla F,　Colombani P,　Cushing B,　Hawkins E,　 et al. Malignant mediastinal germ cell tumors: an intergroup study. J Pediatr Surg.　2001;36:18-24.